About 100,000,000 people have the Type II diabetes mellitus all over the world, which is characterized in hyperglycemia caused by excessive hepatic glucose production and peripheral insulin resistance. The hyperglycemia is considered to be a major risk factor for forming the diabetic complication, and be possibly directly relevant to insulin secretion impairment in the later stage of Type II diabetes mellitus. Therefore, it can be expected that the normalization of insulin can improve the blood glucose in the patients having the Type II diabetes mellitus. The currently known anti-diabetic drugs are mostly insulin secretagogues or euglycemic agents, such as sulfonylureas, glinides, thiazolidinediones and dimethyl biguanides, which have potential side effects such as being apt to increase the body weight, hypoglycemia and lactate acidosis, and therefore there is an urgent need to develop a safe and effective anti-diabetic drug having a new mechanism of action.
In kidney, glucose can filter freely through renal glomerulus (about 180 g/d) but nearly transport actively at proximal convoluted tubule to be reabsorbed. Among others, two sodium-glucose transporters, i.e. SGLT-1 and SGLT-2, have an important effect on the glucose reabsorption, in particular SGLT-2. SGLT-2 is a transmembrane protein only specifically expressed at the S1 section of proximal tubule. One of its major physiological functions is to absorb the glucose in the blood flowing through the renal tubule, which comprises 90% of the reabsorption. SGLT-2 transports at a ratio of 1:1 sodium-glucose. The SGLT-2 inhibitor can inhibit the absorption of blood glucose in the renal tubule so that a great amount of glucose excretes through the urine. SGLT-1 mainly expresses in the distal convoluted tubule, which comprises 10% of the reabsorption. SGLT-1 transports at a ratio of 2:1 sodium-glucose. In addition, SGLT-1 is also found in the intestinal tract and other tissues. These transporters exert their functions via Na+/ATPase pump and transport to the blood via the glucose transporter-2 (GLUT2). This indicates that the most potential drug target is the SGLT-2 transporter, because its absolute re-absorption for glucose in one hand and its merely expression in kidney in the other hand. In the study on the urine glucose from the nephrosis of the familial form, the feasibility of this route has been verified. The urine glucose from the nephrosis of the familial form is mainly manifested as non-quantitative urine glucose (about 10-120 g/d), but the patient has a good general condition and has no chronic negative effect adverse for the health to be found. This benign urine glucose is mainly caused by the genic mutation of the SGLT-2 transporter, which indicates that the selective pharmacological inhibition to SGLT-2 will not produce an adverse effect except for the induction of urine glucose. It has been evidenced that one important clinic advantage for the SGLT-2 inhibitor is the low possibility of hypoglycemia. However, the inhibition of SGLT-1 will cause the glucose-galactose malabsorption syndrome, which may result in the dehydration. In addition, it has also been evidenced that the SGLT-1 inhibitor will defer the absorption of carbohydrates and cause a gastrointestinal symptom that is difficult for an individual to tolerate. A highly selective SGLT-2 inhibitor will not block the action of SGLT-1 absorbing the glucose in the intestinal tract transport, and therefore is not apt to cause the gastrointestinal symptom. In addition, SGLT-1 is also highly expressed in the myocardial tissue of the human body, the blocking of SGLT-1 will possibly cause new or structural disease in the cardiac function. Therefore, the development of a compound having a high selectivity on SGLT-2 has a significant meanings in the research for the drug for treating diabetes mellitus.
Since the SGLT-2 inhibitor acts on SGLT-2 transporter to inhibit the reabsorption of the kidney glucose to treat the high blood glucose, a new route for treating the diabetes mellitus is provided. Although this route cannot directly act on the pathophysiology of Type II diabetes mellitus, however the reduction of blood glucose by increasing the excretion of glucose in kidney can cause the deficiency in the net energy to promote losing the body weight and indirectly improve the obesity conditions. It is found in the study that these drugs, if being used in combination of the existing drug for reducing the blood glucose or the insulin, have a lower risk of the hypoglycemia and a potential effect of losing the weight. The SGLT-2 inhibitor is independent on the function of β-cells and the insulin resistance, therefore it is not only effective for a patient having a general diabetes mellitus, but also has a better therapeutic effect for a patient who has experienced a failed treatment with the drugs such as biguanides and DPP-4 inhibitors. Accordingly, the SGLT-2 inhibitor can be used in combination with the hypoglycemic drug such as biguanides and DPP-4 inhibitors in future.
Among others, the patent literatures such as WO 0127128 and US 2005209166 disclose a series of compounds as SGLT-2 inhibitor.
The present applicant also disclosed a series of C-glucoside derivatives as SGLT-2 inhibitor in the PCT application WO2013/000275A1, in which the compound 4 had a good inhibition effect on SGLT-2 and a good selectivity, and had the following structure:
The compound 4 is a mixture of stereoisomers and has asymmetric centers. Therefore, several optical isomers are present. Considering that many chiral mixture drugs in the prior art have the potential problems such as the toxicity and the side effect that are easily produced and unknown, the reduced drug effectiveness, and the difficulty in the quality controlling, the risks for the research and development of the chiral mixture drug will increase remarkably. Since in comparison with the chiral mixture, the optical pure stereoisomer has the advantages such as being more safe, a lower probability of producing the toxicity and the side effect, a better stability, and the ease for quality controlling, and the optical pure stereoisomer also has the characteristics of the potential improvements in the pharmacodynamics, pharmacokinetics and toxicology, therefore the development of a single stereoisomer having high selectivity on SGLT-2, rapid onset, high effectiveness, good safety and good stability has a significant meanings in the subsequent pharmaceutical research and development and the quality controlling in the production of the marketed drug.